Wermer's syndrome or multiple endocrine neoplasia type 1 (MEN1) is characterized by the neoplastic transformation of parathyroid, pituitary, adrenal, gastric endocrine, and pancreatic islet cells. The gene associated with MEN1, which is inherited as an autosomal dominant, is believed to be a tumor suppressor. Normally tumor suppressors play an important role in the regulation of cell growth; however, in heterozygous individuals, when the normal copy of the gene is mutated through an error in DNA replication, tumor development results.
The MEN1 locus (OMIM * 131100) has been mapped to a minimal interval on chromosome 11q13 bounded centromerically by PYGM (Emmert-Buck M. R. et al. (1996) Science 274:998) and telomerically by D11S4936. The genomic sequence as reconstructed from inserts in YAC, BAC, PAC, and P1 clones consists of 10 exons which encode a 2.8 kb transcript. The sequence mu was assembled from 44 different ESTs in NCBI dbEST and from shotgun sequence assemblies. Northern blots using a 1.9 kb contig of the human sequences showed expression in all tissues tested (pancreas, adrenal medulla, thyroid, small intestine, stomach, spleen, prostate, ovary, in colon and in leukocytes. Five frameshift mutations, three nonsense mutations, two deletions, and two missense alterations in this sequence have been identified (Chandrasekharappa, S. C. et al. (1997) Science 276:404-407).
MEN1 syndrome is known to evolve and worsen over a 30 to 40-year period during which cellular mutations increase and the efficiency of the cellular machinery and its their ability to repair chromosomal lesions decreases. The syndrome begins with transformation of a single cell to hyperplasia and progresses through adenomatous or carcinomatous changes. It is known that the neoplastic process, especially hormone production in one gland or organ, may affect progression and manifestation of MEN1 and associated syndromes in another gland or organ.
Neoplasia of the pancreatic islets is common to 80% of MEN1 patients and tends to occur in parallel with parathyroid problems. The excess hormones commonly produced by pancreatic islet cell are pancreatic polypeptide, gastrin, insulin, vasoactive intestinal peptide, glucagon, and somatostatin. Other peptides such as adrenocorticotropin (ACTH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), calcitonin gene products, neurotensin, and gastric inhibitory peptide, may be produced by MEN1 tumors depending on the stage of the disease. Since some MEN1 neoplasms develop malignant features and metastasize to other organs, aggressive screening and surgical intervention at an early stage are very important.
Syndromes associated with neoplasia of the pancreatic islets include Zollinger-Ellison syndrome, Verner-Morrison syndrome, insulinoma, and glucagonoma. Zollinger-Ellison syndrome is characterized by increased gastric acid production, recurrent peptic ulcers, diarrhea, and esophagitis. Verner-Morrison syndrome appears to be associated with the overproduction of vasoactive intestinal peptide and manifests as watery diarrhea, hypokalemia, hypochlorhydria, hypercalcemia, and systemic acidosis. Insulinomas overproduce insulin and cause symptoms such as nervousness, sweating, palpitations, excessive hunger or weight gain, seizures, and loss of consciousness in the fasting state. Glucagonoma is characterized by symptoms such as hyperglycemia, skin rash, anorexia, glossitis, anemia, depression, diarrhea, and venous thrombosis.
Multicentric pituitary tumors occur in over 50% of mutant MEN1 gene carriers. These tumors may cause galactorrhea-amenorrhea syndrome, acromegaly due to excessive growth hormone or GHRH production, or Cushing's disease attributable to excess amounts of ACTH or CRH. MEN1 also manifests as metastasizing carcinoid tumors of the gastrointestinal system. These tumors commonly result from lesions in stomach or duodenal endocrine cells or originate in the thymus or lung. The carcinoid tumors may or may not be locally invasive, and commonly produce serotonin, calcitonin, or CRH.
The discovery of a new human multiple endocrine neoplasia type 1 protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of multiple endocrine neoplasia.